Epeleuton is a 15‐hydroxy eicosapentaenoic acid ethyl ester, a second‐generation synthetic n‐3 fatty acid derivative of eicosapentaenoic acid. The primary objective was to assess the effect of epeleuton on markers of nonalcoholic fatty liver disease (NAFLD) with post hoc analyses of cardiometabolic markers.

In a multicenter, randomized, double‐blind, placebo‐controlled trial, 96 adults with nonalcoholic fatty liver disease and body mass index 25 to 40 were randomized in a 1:1:1 ratio to receive epeleuton 2 g/day, epeleuton 1 g/day, or placebo for 16 weeks. A total of 27% of patients had diabetes mellitus. Epeleuton 2 g/day significantly decreased triglycerides, very‐low‐density lipoprotein cholesterol, and total cholesterol without increasing low‐density lipoprotein cholesterol. Despite a low mean baseline hemoglobin A1C (HbA1C; 6.3±1.3%), epeleuton 2 g/day significantly decreased HbA1c (−0.4%; P=0.026). Among patients with baseline HbA1c >6.5%, epeleuton 2 g/day decreased HbA1c by 1.1% (P=0.047; n=26). Consistent dose‐dependent reductions were observed for fasting plasma glucose, insulin, and insulin resistance indices. Epeleuton 2 g/day decreased circulating markers of cardiovascular risk and endothelial dysfunction. Epeleuton was well tolerated, with a safety profile not different from placebo.

While epeleuton did not meet its primary endpoints on alanine aminotransferase or liver stiffness, it significantly decreased triglycerides, HbA1C, plasma glucose, and inflammatory markers. These data suggest epeleuton may have the potential for cardiovascular risk reduction and nonalcoholic fatty liver disease by simultaneously targeting hypertriglyceridemia, hyperglycemia, and systemic inflammation. Further trials are planned.

Although the primary endpoints of serum ALT and liver stiffness were not met, its administration was associated with significant dose‐dependent decreases of triglycerides, total cholesterol, and multiple atherogenic lipids without raising LDL‐C. Further studies will be necessary to confirm these hypothesis‐generating findings and investigate the full therapeutic effects of epeleuton for NAFLD treatment, hyperglycemia and diabetes mellitus, dyslipidemia, and prevention of ischemic events.

Ref: https://www.ahajournals.org/doi/10.1161/JAHA.119.016334